Comparative Physicochemical and Biological Characterisation of the Similar Biological Medicinal Product Teriparatide and Its Reference Medicinal Product

Abstract

Background: In January 2017, the European Commission approved Terrosa^® (company code RGB-10) as one of the first biosimilar medicinal products of teriparatide for the same indications as for the reference medicinal product Forsteo^® (Lilly France S.A.S.), which has been on the market in the European Union since 2003. The active pharmaceutical ingredient of the reference medicinal product is the biologically active 1-34 fragment of the endogenous human parathyroid hormone [PTH(1-34)]. It is one of the three bone anabolic agents used in the treatment of osteoporosis promoting bone formation and preventing fragility fractures.

Objective: The objective of this paper is to summarise the results of the comparative analysis of representative batches of both the RGB-10 drug product and the reference medicinal product performed by physicochemical and in vitro biological methods.

Methods: A series of state-of-the-art analytical methods were applied in a comparative head-to-head manner for testing the similarity in respect to purity, content, structure and potency.

Results: Based on the results of the comprehensive physicochemical and biological characterisation, RGB-10 proved to be highly similar to the reference medicinal product with respect to the critical quality attributes investigated.

Conclusion: The results of the quality comparability study demonstrated similarity of RGB-10 to the reference medicinal product, providing the scientific basis for conducting a specifically designed clinical programme, and supported registration of the Marketing Authorisation Application of RGB-10 in the EU.

Fig. 1

UV peptide mapping chromatograms (215 nm) of the Glu-C digested samples of RGB-10 and RMP drug products. Major components: G1: 20–22, G2: 1–4, G3: 31–34, G4: 23–30, G5: 23–34, G6: 5–19, G7: 5–22 peptide fragments. M metacresol, RMP reference medicinal product

Fig. 2

CD spectra of RGB-10 and the RMP in different media: a in PBS, b in PBS-TFE (1:1). CD circular dichroism, PBS phosphate-buffered saline, RMP reference medicinal product, TFE trifluoroethanol

Fig. 3

The 2D ¹H-¹⁵N HMQC NMR spectra of RGB-10 and RMP show high level of similarity of the primary and the higher order structures of the DPs. DPs drug products, HMQC heteronuclear multiple quantum coherence, NMR nuclear magnetic resonance spectroscopy, RMP reference medicinal product

Fig. 4

Reversed-phase high-performance liquid chromatography (RP-HPLC) chromatograms of RGB-10 and the reference medicinal product (RMP)

Fig. 5

Ion-exchange high-performance liquid chromatography (IEX-HPLC) chromatograms of RGB-10 and the reference medicinal product (RMP)

Fig. 6

Representative figure (dose–response curves) of side-by-side cAMP-release assay (UMR-106 cells) of RGB-10 (blue, left graph) and reference medicinal product (RMP) (red, right graph) analysed relative to reference standard (black)

Fig. 7

Representative figure (dose–response curves) of side-by-side cAMP-release assay (Saos-2 cells) of RGB-10 (blue, left graph) and reference medicinal product (RMP) (red, right graph) analysed relative to reference standard (black)

Fig. 8

Representative figure (dose–response curves) of side-by-side receptor-binding assay of RGB-10 (blue, left graph) and reference medicinal product (RMP) (red, right graph) analysed relative to reference standard (black)

Fig. 9

Representative figure (dose–response curves) of side-by-side enzyme-linked immunosorbent assay (ELISA) of reference medicinal product (RMP) (red) and RGB-10 (blue) analysed relative to reference standard (black) to reveal specific immunologic reactivity